# Therapeutic Targeting of Mitochondria in Uromodulin-Associated Chronic Kidney Disease

> **NIH VA I01** · ST. LOUIS VA MEDICAL CENTER · 2024 · —

## Abstract

Uromodulin (UMOD)-associated chronic kidney disease (CKD), or autosomal dominant tubulointerstitial kidney
disease caused by UMOD mutations (ADTKD-UMOD), is characterized by progressive renal fibrosis and CKD.
Currently there is no targeted therapy. The disease is frequently manifested until adulthood and its prevalence
has been significantly underestimated in Veterans. Moreover, genetic variants in the UMOD locus have the
largest effect on kidney function and CKD progression in both general population and Veterans, and UMOD
genetic variants with unknown function have also been identified with high frequency in hypertensive and
diabetic kidney disease, the most common causes of CKD and kidney failure among Veterans and the general
American population. However, the functional significance of these UMOD variants remains elusive. Thus, our
research on the UMOD genetic variants will contribute to the improvement of Veteran’s health significantly.
 To address the unmet medical needs, by using CRISPR/Cas9 we have developed a mouse model carrying
Umod p.Tyr178_Arg186 del, the mouse equivalent of the most prevalent human mutation. UMOD is primarily
synthesized and secreted by the tubular cells of thick ascending limb (TAL) of Henle’s loop. We demonstrate
that defective mitochondrial biogenesis, oxidative phosphorylation (OXPHOS) and mitophagy in the mutant
TALs lead to activation of STING (stimulator of interferon genes)-mediated inflammation, eventually causing
TAL cell death and renal fibrosis. More importantly, we have discovered a novel biotherapeutic protein,
mesencephalic astrocyte-derived neurotrophic factor (MANF) that can positively modulate mitochondrial quality
control and mitigate STING-induced inflammation and fibrosis in our ADTKD mouse model. Additionally, we
provide compelling data that blockade of MANF receptor neuroplastin preserves mitochondrial function and
that inhibition of the STING pathway suppresses mitochondria-dependent inflammation in our mutant UMOD
cell model.
 The overall goal of this VA Merit application is to develop novel therapies to restore mitochondrial function
and alleviate mitochondria-mediated inflammation by targeting MANF and neuroplastin, as well as STING
pathway in ADTKD. Our overarching hypothesis is that promoting mitochondrial homeostasis is a novel
therapeutic strategy to treat ADTKD-UMOD and CKD. To accomplish our research goals and test our
hypothesis, we have assembled an interdisciplinary team including multiple Co-Investigators and cores with
various innovative technologies and required expertise.
 The proposed study will provide critical insights into the molecular pathogenesis of ADTKD and other forms
of organelle stress-induced CKD, as well as discover mitochondria-targeted and mechanism-based novel
treatments for ADTKD and CKD in Veterans.

## Key facts

- **NIH application ID:** 10923602
- **Project number:** 1I01BX006401-01A1
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Ying Maggie Chen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923602

## Citation

> US National Institutes of Health, RePORTER application 10923602, Therapeutic Targeting of Mitochondria in Uromodulin-Associated Chronic Kidney Disease (1I01BX006401-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10923602. Licensed CC0.

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